scholarly journals Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 445
Author(s):  
Daniela Zizioli ◽  
Simona Bernardi ◽  
Marco Varinelli ◽  
Mirko Farina ◽  
Luca Mignani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Leukemic Cells ◽  
Transgenic Zebrafish ◽  
Hematopoietic Tissue ◽  
Zebrafish Model ◽  
Altered Expression

Zebrafish has proven to be a versatile and reliable experimental in vivo tool to study human hematopoiesis and model hematological malignancies. Transgenic technologies enable the generation of specific leukemia types by the expression of human oncogenes under specific promoters. Using this technology, a variety of myeloid and lymphoid malignancies zebrafish models have been described. Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR-ABL1 fusion gene, derived from the t (9;22) translocation causing the Philadelphia Chromosome (Ph). The BCR-ABL1 protein is a constitutively activated tyrosine kinas inducing the leukemogenesis and resulting in an accumulation of immature leukemic cells into bone marrow and peripheral blood. To model Ph+ CML, a transgenic zebrafish line expressing the human BCR-ABL1 was generated by the Gal4/UAS system, and then crossed with the hsp70-Gal4 transgenic line. The new line named (BCR-ABL1pUAS:CFP/hsp70-Gal4), presented altered expression of hematopoietic markers during embryonic development compared to controls and transgenic larvae showed proliferating hematopoietic cells in the caudal hematopoietic tissue (CHT). The present transgenic zebrafish would be a robust CML model and a high-throughput drug screening tool.

MYST3/NCOA2-Induced Acute Myeloid Leukemia in Transgenic Fish

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5329-5329
Author(s):  
Julia Zhuravleva ◽  
Jérôme Paggetti ◽  
Laurent Martin ◽  
Arlette Hammann ◽  
Eric Solary ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Transgenic Expression ◽  
Acute Myeloid

Abstract The MYST3/NCOA2 (MOZ/TIF2) fusion gene generated by the inv(8)(p11q13) chromosomal abnormality was described in a specific subgroup of acute myeloid leukemias (AML) that represents less than 5% of AML4/5. This abnormality fuses MYST3 (MOZ), a member of the MYST family of histone acetyl-transferases (HAT) to NCOA2 (TIF2), a member of the p160 HAT family. The transforming properties of MYST3/NCOA2 were demonstrated in mouse committed myeloid progenitors in vitro and in vivo. Hematopoiesis is very similar in zebrafish and in higher vertebrates. Homologues of a large number of genes involved in mammalian myelopoiesis were identified in this animal model. We have recently shown that ncoa2 (tif2) played a role in zebrafish primitive hematopoiesis. This animal also represents a model for investigating leukemogenesis. Transgenic expression of rag2-EGFP-mMyc or rag2-ICN1-EGFP induces a T-cell acute lymphoblastic leukemia (ALL) whereas transgenic expression of the ETV6/RUNX1 fusion gene induces a B-cell type ALL. We generated a transgenic zebrafish in which the MYST3/NCOA2 fusion gene was expressed under control of the spi1 (pu.1) promoter. An AML developed in two of 180 MYST3/NCOA2-EGFP-expressing embryos, 14 and 26 months after injection of the fusion gene in a one cell embryo, respectively. This leukemia was characterized by an extensive invasion of kidneys by myeloid blast cells. This model, which is the first zebrafish model of acute myeloid leukemia, demonstrates the oncogenic potency of MYST3/NCOA2 fusion gene.

THE CASE VARIANT TRANSLOCATION T(3;9;22)(P24;Q34;Q11) IN CHRONIC MYELOID LEUKEMIA

2018 ◽  
Vol 64 (6) ◽  
pp. 810-814
Author(s):  
Kodirzhon Boboev ◽  
Yuliana Assesorova ◽  
Kh. Karimov ◽  
B. Allanazarova
Keyword(s):  
Adverse Effect ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Genetic Locus ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Banding Technique ◽  
Variant Translocation

This paper presents a case of chronic myeloid leukemia with an earlier unknown variant translocation t (3; 9; 22) (p24; q34; q11) detected by cytogenetic research using the GTG-banding technique. Despite the absence of the classical Philadelphia chromosome, the presence of chromosome 9 and 22 derivatives, as well as the BCR-ABL fusion gene, allow this translocation to be considered pathogenetic for CML. A good response of the patient to the treatment with glivec is that there is no adverse effect on the pathogenesis of the disease of an additional genetic locus (3p24) involved in complex restructuring.

Effect of Dasatinib on Genes Related to Mitotic Catastrophe Pathway in Chronic Myeloid Leukemia Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Sezgi Kipcak ◽  
Buket Ozel ◽  
Cigir B. Avci ◽  
Leila S. Takanlou ◽  
Maryam S. Takanlou ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
K562 Cells ◽  
Mitotic Catastrophe ◽  
Control Group ◽  
Cancer Therapies ◽  
Apoptosis Pathways

Background: Chronic myeloid leukemia (CML), is characterized by a reciprocal translocation t(9;22) and forms the BCR/ABL1 fusion gene, which is called the Philadelphia chromosome. The therapeutic targets for CML patients which are mediated with BCR/ABL1 oncogenic are tyrosine kinase inhibitors such as imatinib, dasatinib, and nilotinib. The latter two of which have been approved for the treatment of imatinib-resistant or intolerance CML patients. Mitotic catastrophe (MC) is one of the non-apoptotic mechanisms which frequently initiated in types of cancer cells in response to anti-cancer therapies; pharmacological inhibitors of G2 checkpoint members or genetic suppression of PLK1, PLK2, ATR, ATM, CHK1, and CHK2 can trigger DNA-damage-stimulated mitotic catastrophe. PLK1, AURKA/B anomalously expressed in CML cells, that phosphorylation and activation of PLK1 occur by AURKB at centromeres and kinetochores. Objective: The purpose of this study was to investigate the effect of dasatinib on the expression of genes in MC and apoptosis pathways in K562 cells. Methods: Total RNA was isolated from K-562 cells treated with the IC50 value of dasatinib and untreated cells as a control group. The expression of MC and apoptosis-related genes were analyzed by the qRT-PCR system. Results: The array-data demonstrated that dasatinib-treated K562 cells significantly caused the decrease of several genes (AURKA, AURKB, PLK, CHEK1, MYC, XPC, BCL2, and XRCC2). Conclusion: The evidence supply a basis to support clinical researches for the suppression of oncogenes such as PLKs with AURKs in the treatment of types of cancer especially chronic myeloid leukemia.

scholarly journals Ph-negative chronic myeloid leukemia: molecular analysis of ABL insertion into M-BCR on chromosome 22

Blood ◽  
1990 ◽  
Vol 76 (9) ◽  
pp. 1812-1818 ◽  
Author(s):  
CM Morris ◽  
N Heisterkamp ◽  
MA Kennedy ◽  
PH Fitzgerald ◽  
J Groffen
Keyword(s):  
In Situ Hybridization ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Repetitive Sequences ◽  
Chromosome 9 ◽  
Leukemic Cells ◽  
Chromosome 22 ◽  
Chromosome 9Q34

Abstract Leukemic cells from a patient with Ph-negative chronic myeloid leukemia (CML) had a normal karyotype. M-BCR was rearranged and chromosome in situ hybridization showed an ABL insertion between 5′ and 3′ M-BCR on an apparently normal chromosome 22. The association of 5′ BCR and 3′ ABL at the 5′ junction of the chromosome 9 insert was typical of that found for the BCR-ABL fusion gene in other patients with the standard t(9;22) and CML. With an M-bcr-3′ probe, we cloned and characterized a 3′ junction fragment. Field inversion gel electrophoresis and chromosome in situ hybridization studies using a probe isolated from genomic DNA 5′ of the junction showed that 3′ M-BCR was joined to a region of chromosome 9q34 rich in repetitive sequences and lying some distance 3′ of ABL. The chromosome 9 insert was at least 329 kilobases long and included 3′ ABL and a larger portion of chromosome 9q34. Our results allowed us to exclude transposon- or retroviral-mediated insertion of ABL into chromosome 22. Instead, we favored a two- translocation model in which a second translocation reconstituted a standard t(9;22)(q34;q11) but left the chromosome 9 insert, including 3′ ABL, in chromosome 22.

α1-Acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 713-715 ◽  
Author(s):  
Heather G. Jørgensen ◽  
Moira A. Elliott ◽  
Elaine K. Allan ◽  
Christine E. Carr ◽  
Tessa L. Holyoake ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Proteins ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Drug Efficacy ◽  
Acid Glycoprotein ◽  
Proliferation In Vitro ◽  
Normal Controls

Abstract Despite the efficacy of STI571 (Glivec, Novartis, Basle, Switzerland) in treating chronic myeloid leukemia (CML), drug resistance has already been noted both in vitro and in vivo. As plasma proteins, including alpha-1-acid glycoprotein (AGP), may reduce drug efficacy through binding, AGP was investigated for its ability to interact with STI571.  At all stages of CML, AGP plasma level was significantly higher than in normal controls (P < .05). The glycoprotein was purified from normal plasma and individual chronic myeloid leukemia (CML) patients' plasma by low-pressure chromatography. The influence of α1-acid glycoprotein (AGP), in the presence of STI571, on the proliferation of Philadelphia chromosome–positive (Ph+) cells was examined. Normal AGP, even at supraphysiological concentrations, did not block the effect of STI571 on K562-cell proliferation in vitro. Moreover, CML-derived AGP failed to block the effect of STI571 on Ph+ cells in vitro. Thus, these in vitro findings suggest that AGP will not abrogate the antileukemic activity of STI571.

scholarly journals P210 and P190 BCR-ABL fusion transcripts variants frequencies among Philadelphia chromosome-positive chronic myeloid leukemia in Sudan

2018 ◽  
Vol 9 (5) ◽  
pp. 172
Author(s):  
Abdalla Abdelrahman Ahmed Elnour ◽  
Mahdi H.A. Abdalla
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Chronic Myelogenous Leukaemia ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Fusion Transcript ◽  
Specific Primers ◽  
Transcript Variants

Breakpoint cluster region-abelson (BCR-ABL) leukemic fusion gene types in chronic myeloid leukemia (CML) correlate with the disease clinical course and outcome. There are variations in the reports of previous studies about the frequencies and distribution of BCR-ABL transcripts in chronic myelogenous leukaemia among Sudanese patients. This research aims to determine the frequencies of BCR-ABL fusion transcript variants in Sudan. One hundred (informed consent) Philadelphia positive chronic myeloid leukaemia patients, in chronic phase, were enrolled in this study. EDTA anticoagulated peripheral blood samples were collected from each participant, RNA was extracted from mononuclear cells by (TRIzol) reagent. BCR-ABL transcripts were detected by qRT-PCR technique with specific primers forP190 and P210 BCR-ABL transcript variants. The typical p210 BCR-ABL transcripts (b3a2 or b2a2) were detected in all patients (100%) the b3a2 transcript was detected in 96/100 (96%) and the b2a2 transcript was detected in 4/100 (4%).co-expression of p210/p190 (b2a3/e1a2) was detected in 6/100 (6%). p190 variant was not detected independently. 

scholarly journals Phenotypic heterogeneity of primitive leukemic hematopoietic cells in patients with chronic myeloid leukemia

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2522-2530 ◽  
Author(s):  
C Udomsakdi ◽  
CJ Eaves ◽  
PM Lansdorp ◽  
AC Eaves
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Significant Proportion ◽  
Hematopoietic Cells ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Clonogenic Cell ◽  
Clonogenic Cells

Abstract The peripheral blood of chronic myeloid leukemia (CML) patients with chronic-phase disease and elevated white blood cell (WBC) counts typically contains markedly increased numbers of a variety of neoplastic pluripotent and lineage-restricted hematopoietic progenitors. These include cells detected in standard colony assays as well as their more primitive precursors. The latter are referred to as long-term culture-initiating cells (LTC-IC) because of their ability to generate clonogenic cell progeny detectable after a minimum of 5 weeks incubation on competent fibroblast feeder layers. In this study, we have investigated a number of the properties of the LTC-IC and clonogenic cells present in the blood of such CML patients with high WBC counts. This included an analysis of the light scattering properties of these progenitors, as well as their expression of CD34 and HLA-DR, Rhodamine-123 staining, and in vitro sensitivity to 4- hydroperoxycyclophosphamide. In the case of LTC-IC, the production of different types of lineage-restricted and multipotent progeny was also analyzed. Most of the circulating LTC-IC and clonogenic cells in the CML patients studied (on average approximately 70% and approximately 90%, respectively) showed features of proliferating or activated cells. This is in marked contrast to the majority of progenitors in the blood of normal individuals and most of the LTC-IC in normal marrow, all of which exhibit a phenotype expected of quiescent cells. Interestingly, a significant proportion of the circulating clonogenic cells and LTC-IC in the CML samples studied (on average approximately 10% and approximately 30%, respectively) appeared to be phenotypically similar to normal circulating progenitors, although their absolute numbers were indicative of a neoplastic origin. Both phenotypes of circulating CML clonogenic cells and LTC-IC could be obtained at approximately 10% to 20% purity by differential multiparameter sorting. These findings suggest that expansion of the Philadelphia chromosome-positive clone at the level of the earliest types of hematopoietic cells results from the activation of mechanisms that enable some, but not all, signals that block the cycling of normal stem cells to be bypassed or overcome. In addition, they provide strategies for purifying these primitive leukemic cells that should facilitate further analysis of the mechanisms underlying their abnormal proliferative behavior.

scholarly journals Live imaging of neutrophil motility in a zebrafish model of WHIM syndrome

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2803-2811 ◽  
Author(s):  
Kevin B. Walters ◽  
Julie M. Green ◽  
Jill C. Surfus ◽  
Sa Kan Yoo ◽  
Anna Huttenlocher
Keyword(s):  
Primary Immunodeficiency ◽  
Transgenic Zebrafish ◽  
Hematopoietic Tissue ◽  
Primary Immunodeficiency Disorder ◽  
Zebrafish Model ◽  
Whim Syndrome ◽  
Stromal Cell Derived Factor ◽  
Morpholino Oligonucleotides ◽  
Guanosine Triphosphatase

Abstract CXCR4 is a G protein–coupled chemokine receptor that has been implicated in the pathogenesis of primary immunodeficiency disorders and cancer. Autosomal dominant gain-of-function truncations of CXCR4 are associated with warts, hypo-gammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a primary immunodeficiency disorder characterized by neutropenia and recurrent infections. Recent progress has implicated CXCR4-SDF1 (stromal cell-derived factor 1) signaling in regulating neutrophil homeostasis, but the precise role of CXCR4-SDF1 interactions in regulating neutrophil motility in vivo is not known. Here, we use the optical transparency of zebrafish to visualize neutrophil trafficking in vivo in a zebrafish model of WHIM syndrome. We demonstrate that expression of WHIM mutations in zebrafish neutrophils induces neutrophil retention in hematopoietic tissue, impairing neutrophil motility and wound recruitment. The neutrophil retention signal induced by WHIM truncation mutations is SDF1 dependent, because depletion of SDF1 with the use of morpholino oligonucleotides restores neutrophil chemotaxis to wounds. Moreover, localized activation of a genetically encoded, photoactivatable Rac guanosine triphosphatase is sufficient to direct migration of neutrophils that express the WHIM mutation. The findings suggest that this transgenic zebrafish model of WHIM syndrome may provide a valuable tool to screen for agents that modify CXCR4-SDF1 retention signals.

scholarly journals Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 120 (5) ◽  
pp. 1107-1117 ◽  
Author(s):  
Satomi Tanaka ◽  
Satoru Miyagi ◽  
Goro Sashida ◽  
Tetsuhiro Chiba ◽  
Jin Yuan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Fusion Gene ◽  
Hematologic Malignancies ◽  
Leukemic Cells ◽  
Polycomb Repressive Complex 2 ◽  
Acute Myeloid

Abstract EZH2, a catalytic component of the polycomb repressive complex 2, trimethylates histone H3 at lysine 27 (H3K27) to repress the transcription of target genes. Although EZH2 is overexpressed in various cancers, including some hematologic malignancies, the role of EZH2 in acute myeloid leukemia (AML) has yet to be examined in vivo. In the present study, we transformed granulocyte macrophage progenitors from Cre-ERT;Ezh2flox/flox mice with the MLL-AF9 leukemic fusion gene to analyze the function of Ezh2 in AML. Deletion of Ezh2 in transformed granulocyte macrophage progenitors compromised growth severely in vitro and attenuated the progression of AML significantly in vivo. Ezh2-deficient leukemic cells developed into a chronic myelomonocytic leukemia–like disease with a lower frequency of leukemia-initiating cells compared with the control. Chromatin immunoprecipitation followed by sequencing revealed a significant reduction in the levels of trimethylation at H3K27 in Ezh2-deficient leukemic cells, not only at Cdkn2a, a known major target of Ezh2, but also at a cohort of genes relevant to the developmental and differentiation processes. Overexpression of Egr1, one of the derepressed genes in Ezh2-deficient leukemic cells, promoted the differentiation of AML cells profoundly. Our findings suggest that Ezh2 inhibits differentiation programs in leukemic stem cells, thereby augmenting their leukemogenic activity.

scholarly journals Nursing Care Management of Chronic Myeloid Leukemia – A Case Report

2021 ◽  
Vol 10 (16) ◽  
pp. 1182-1184
Author(s):  
Shakib Hasan Sheikh ◽  
Vaishali Tembhare ◽  
Seema Singh ◽  
Savita Pohekar ◽  
Samruddhi Gujar
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Normal Cell ◽  
Care Management ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Lymphocytic Leukemia ◽  
Ph Chromosome ◽  
Normal Cell Cycle

Excessive growth of mature granulocytes in the bone marrow induces chronic myeloid leukemia. The excess neoplastic granulocytes travel massively into the peripheral blood and in the end invade the liver and spleen. The protein encoded on the Philadelphia chromosome by the newly created BCR-ABL gene interferes with normal cell cycle activities, including regulating cell proliferation. Philadelphia chromosome is present in 90 - 95 percent of chronic myeloid leukemia (CML) patients. Their involvement is often a vital indicator of persistent disease or posttreatment relapse. However, for the diagnosis of CML, the presence of the Philadelphia chromosome is not specific since it is also present in acute lymphocytic leukemia (ALL) and rarely in acute myeloid leukemia (AML). 1 Chronic myeloid leukemia is a myeloproliferative neoplasm (MPN) characterised by involvement of the fusion gene BCRABL1 located in the Philadelphia chromosome. In reactive neutrophilia or chronic neutrophilic leukemia, the Ph chromosome is pathognomonic to CML and is never registered.2,3

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